1. Field of the Invention
The present invention relates to certain chiral nucleotide analogs and their compositions and use in the treatment of viral infections. In particular, the present invention relates to certain chiral acyclic treatment of human immunodeficiency virus (HIV) diseases.
2. Information Disclosure Statement
Infectious viral diseases are recognized as an important medical problem. Progress against infectious viral diseases requires the development of drugs with selective antiviral activity while remaining benign to normal cell lines. A number of antiviral agents currently under study, which seem to possess some selectivity, are nucleoside analogs. In general, these compounds are structural analogs of the naturally occurring nucleosides. Structural modification in either the purine or pyrimidine base nucleus and/or the saccharide component results in a synthetically modified nucleoside derivative which, when incorporated into a viral nucleic acid forming process, acts to disrupt further synthesis of viral nucleic acid. Effectiveness of these antiviral agents depends on selective conversion by viral enzymes, but not by host enzymes, to the corresponding nucleotide analog which is then converted to the triphosphate and incorporated into viral nucleic acid. A problem with this antiviral strategy has been the emergence of certain viral strains whose enzymes poorly promote phosphorylation of the nucleoside analogs. To circumvent this problem, intact nucleotide analogs appear to be potentially quite useful as antivirals for incorporation into viral nucleic acid.
Reist and Sturm in PCT/U.S. 84/00737, published Dec. 6, 1984, disclosed new phosphonic acid analogs of nucleoside phosphates which are useful as antivirals for incorporation into viral DNA. The structural formula for these compounds is shown below as Formula 1. ##STR2##
In the Reist compounds, B is a purine or pyrimidine base: R.sub.1 and R.sub.2 together complete a .beta.-pentofuranose sugar or R.sub.1 is H and R.sub.2 is H or hydroxymethyl; R.sub.3 is H or OH; X is H, OH, or together with Y is carbonyl oxygen, and Y can also be H; Z.sub.1 and Z.sub.2 are H or alkyl. These art compounds are generally distinguished from the compounds of the instant invention by (a) the ether-oxygen link to the carbon atom attached to the base which is intended to preserve or mimic the acetal oxygen bond of a pentofuranose sugar ring and (b) the phosphate modification which is a phosphonoalkylene moiety. In contrast, the acyclic sugar analog component of the instant compounds is comprised of an all carbon atom backbone up to a phosphonomethoxy moiety.
Similarly, synthesis and anti-Herpes virus activity of phosphate and phosphonate derivatives of 9-[(1,3-dihydroxy-2-propoxy)methyl]guanine (Formula 2) were disclosed by Prisbe, et al., in J. Med. Chem., 1986, 29, 671. ##STR3##
More closely related are adenine phosphonic acid analogs (Formula 3) and their syntheses which were disclosed in the United Kingdom patent application of Holy, et al.. GB 2,134,907A, published on August 22, 1984, and its related U.S. Pat. No. 4,659,825. ##STR4##
In Formula 3, R.sub.2 and R.sub.3 may be hydrogen and R.sub.4 is independently a hydrogen atom or a --CH.sub.2 P(O)(OH).sub.2 group.
A preferred example of one of these compounds, known as (S)-HPMPA (Formula 4), was disclosed by E. DeClercq, et al., in Nature, 1986, 323, pp. 464-467, and in Antiviral Research, 1987, 8, pp. 261-272, and earlier by A. Holy, et al., Nucleic Acids Research, Symposium Series No. 14, 1984, pp. 277-278. The reported antiviral activity of HPMPA resides only in the isomer having the (S)-configuration at the chiral center on the side chain. The corresponding (R)-isomer is reported to be devoid of antiviral activity. ##STR5##
European Patent Application EP-253,412 of A. Holy, et al., published on Jan. 20, 1988, discloses a series of N-phosphonylmethoxyalkyl derivatives of pyrimidine and purine bases (Formula 5) exhibiting antiviral activity ##STR6## in which R is a hydrogen atom or a hydroxymethyl group and B is an optionally substituted pyrimidin-1-yl, pyrimidin-3-yl, purin-3-yl, purin-7-yl, or purin-9-yl residue, whereby unsubstituted adenin-9-yl is excluded. Substituent B is preferably, inter alia, guanin-9-yl. One of the examples wherein B is guanin-9-yl and R is --CH.sub.2 OH (HPMPG) is disclosed only as the racemic (RS)-isomer.
European Patent Application EP-269,947 of R. R. Webb, II, et al., published on Jun. 8, 1988, discloses a series of phosphonomethoxyalkene purine and pyrimidine derivatives which are useful as antiviral agents and have the general Formula 6 ##STR7## wherein B is a purine or pyrimidine base; alk.sub.1, alk.sub.2, and alk.sub.3 are chemical bonds or alkylene groups; Q is hydrogen or hydroxy; and R.sub.1 -R.sub.4 are hydrogen or alkyl, provided that B is not 9-adenyl when R.sub.1 -R.sub.4 is hydrogen and alk.sub.1, alk.sub.2, alk.sub.3, and Q are as disclosed by A. Holy, et al., GB 2,134,907, cited above. There is also generically disclosed in European Patent Application EP-269,947 as Example 32 and Example 35 in Table 1 and in claim 8 the racemic compound of the present invention. The racemic compound of the present invention was never made and was suggested as only one of many possible combinations.
In Nucleotide Analogs as Antiviral Agents; ACS Symposium Series 401; Martin, J. C. Ed.: Washington, D.C., 1989, Chapter 5, pp. 72-87; J. J. Bronson, et al., report on the series of nucleotide analogs disclosed in the above cited European Patent Application EP-269,947 publication. Also, in J. Med. Chem., 1990, 33, 1207-1213, C. U. Kim, et al., describes a similar series of compounds.
The present applicants have separately prepared the (R)- and (S)-isomers of 9-[2-(phosphonomethoxy)propyl]guanine (2'-methyl-PMEG) and have discovered, surprisingly, that both are active against human immunodeficiency virus (HIV). In sharp contrast, as disclosed in the present invention, both the (R)- and (S)-isomers of HPMPG are inactive against HIV. More surprising was the unexpected finding that the (R)-isomer of 2'-methyl-PMEG provides complete protection of both MT4 and CEM-SS cells against HIV over a concentration range of from about 5 to 100 .mu.M with no observable cytotoxicity at concentrations less than 100 .mu.M. In contrast, PMEG is approximately 30 fold more cytotoxic than (R)-2'-methyl-PMEG.
There is no teaching contained in these references, or combination thereof, which would make obvious the use of the instant compounds against HIV infections. Furthermore, there is no teaching which would suggest the preparation of one specific isomer and that one isomer would provide both unexpected lower toxicity and greater selectivity as an anti-HIV agent.